Effect of medicinal herbs on primary dysmenorrhoea- a systematic review.

Conventional treatment for primary dysmenorrhoea has a failure rate of 20% to 25% and may be contraindicated or not tolerated by some women. Herbal medicine may be a suitable alternative. To determine the efficacy and safety of Iranian herbal medicine for primary dysmenorrhea when compared with placebo, no treatment, and other treatment. Electronic searches of the Cochrane Menstrual Disorders and Dysmenorrhoea Group Register of controlled trials, Scopus, Google Scholar, Medline, Pubmed were performed to identify relevant randomized controlled trials (RCTs). The study abstraction and quality assessment of all studies were undertaken following the detailed descriptions of these categories as described in the JADAD Criteria for Systematic Reviews of Interventions. 25 RCTs involving a total of women were included in the review. The review found promising evidence in the form of RCTs for the use of herbal medicine in the treatment of primary dysmenorrhoea compared with pharmacological treatment. However, the results were limited by methodological flaws. Further rigorous no penetrating placebo-controlled RCTs are warranted. The review found promising evidence supporting the use of herbal medicine for primary dysmenorrhoea; however, results are limited by the poor methodological quality of the included trials.


Introduction
There are about 8000 species of herbs in Iran, of which 1300 are endemic to Iran. Most consumers of medicinal plants are women who use them to alleviate problems such as menstrual disorders, mood disorders and menopause disorders, cyclical mastalgia and dysmenorrhea. They use these products more than chemical drugs because of being natural and having fewer side effects (1).
The term dysmenorrhea refers to painful menstruation. Dysmenorrhea is a cramp labor-like pain in the lower abdomen that radiates to upper abdomen, waist and thighs and is sometimes accompanied by systemic symptoms like nausea, vomiting, diarrhea, headache and dizziness (2, 3).
In terms of blinding, there were 4 triple-blind studies, 8 randomized double-blind clinical trials, 5 randomized single-blind clinical trials and 7 unblinded studies.
Foeniculum vulgare F. vulgare is from Apiaceae family whose root, leaf and fruit can be used. This plant has been used in Iranian traditional medicine for many centuries and has anti-inflammatory, analgesic and antispasmodic effects (8).
The mechanism of its analgesic effect is explained in two ways: 1.
The essential oil of this product has analgesic effects in uterus by inhibiting contractions induced by oxytocin and prostaglandins.
2. This product facilitates discharge of blood in shorter time, which reduces dysmenorrhea (9).
Eight studies have examined the effect of F. vulgare on primary dysmenorrheal. Three of them compared the effect of F. vulgare with placebo (10-12), two compared the effect of F. vulgare with mefenamic acid (13 and 14) and one compared the effect of F. vulgare and placebo with mefenamic acid (15).
In one study, the effect of F. vulgare and M. chamomoilla (16) and in another, the effect of F. vulgare and E. platyloba were compared (17). Khorshidi et al. showed that F. vulgare essential oil was useful in reducing pain and systemic symptoms of primary dysmenorrheal compared with placebo (11), but in the study by Zahrani et al., F. vulgare did not affect systemic having severe dysmenorrhea (4, 5).
In dealing with dysmenorrhea, medications such as prostaglandin synthesis inhibitors, nonsteroidal anti-inflammatory drugs and contraception pills are used irregularly because of fear of their side effects. Also, some of them have not been accepted in Iranian culture. Therefore, it seems necessary to find a new and simpler treatment for dysmenorrhea (6).
Some herbal products are effective on dysmenorrhea and its associated symptoms. Some plants are anti-spasmodic and some have a prostaglandin inhibitory effect. The mechanism of action of many herbal medicines is not completely understood.
Regarding the increasing demand for herbal medicine, many studies have been conducted on the analgesic effect of herbal extracts in Iran, but this is the first systematic review article in this field. This study aimed to systematically review and summarize analysis of clinical trials in this context and to investigate safety and efficacy of various methods for relieving dysmenorrhea.

Methods
All clinical trials of herbal products in treatment of primary dysmenorrheawere studied. Studies with inclusion criteria of women at reproductive age with moderate to severe primary dysmenorrhea and with regular menstrual periods as well as exclusion criteria of mild dysmenorrhea, irregular menstrual periods and obligation to use a particular drug entered this systematic review.
Databases such as Scopus, Google Scholar and Pubmed were searched and articles were evaluated according to Jadad Scale (7). This scale investigates articles based on probability of randomization error, patient's follow-up and blinding. In this scale, the maximum score is 5. The papers which had scores of 3 or more were examined in this study. The results are presented qualitatively.

Results
The systematic search primarily investigated clinical trials of herbal products (investigating    F. vulgare has been effective in reducing severity of dysmenorrhea in all studies; in comparative studies with mefenamic acid, there has been no significant difference between the two groups in terms of reducing dysmenorrheal (Table 1).
Zingiber officinale Z. officinale has a long history in medicine and is one of the potent inhibitors of prostaglandins (via cyclooxygenase inhibition). In some sources, one of the traditional uses of Z. officinale is for treating dysmenorrhea. (18) In a double-blind clinical trial, the effect of Z. officinale was compared with that of mefenamic acid and ibuprofen for treatment of primary dysmenorrhea and there was no significant difference in the improvement of primary dysmenorrhea in three groups of Z. officinale (64%), ibuprofen (66%) and mefenamic acid (58%). In other words, Z. officinale was effective in the treatment of primary dysmenorrhea like two conventional chemical drugs (18). In another study, rhizome powder of Z. officinale was effective for reducing pain intensity in Menastil ® Menastil ® containing calendula oil and mint essential oil. Menastil ® prevents transmission of messages from nerve cells of uterus to brain by shortening axons of nerve cells and leads to late transfer of pain messages from brain to uterus (20).
In a clinical trial, topical use of Menastil lotions was more effective than placebo in reducing severity of dysmenorrhea and its symptoms. Furthermore, sedative consumption and menstrual bleeding decreased (21).
Cumminum cyminum C. cyminum is useful for treatment of gastrointestinal diseases, delayed and painful menstruation. In a randomized clinical trial, patients were divided to 5 groups. Three groups consumed 65 mg of C. cyminum capsules (1 capsule/TID, 2 capsules/TID and, the 3 rd group, 1 capsule/BID), one group consumed a placebo capsule and the last group took mefenamic acid. Finally, among consumers of C. cyminum, those who had 2 capsules/ TID had minimal pain, which was equal to those who consumed mefenamic capsule per 8 h. Furthermore, there was a significant differenceamong the three groups in terms of reducing pain intensity in the first and second periods after the treatment compared withthat before intervention (22).

Menstrugol ® (saffron, celery and aniseed)
In a clinical trial, an herbal capsule (Menstrugol ® ) containing extract of 3 plants (saffron, celery and aniseed) worked for primary dysmenorrhea and had better and more proper effects than mefenamic acid (23).
In another study, this extract was more effective than placebo on severity of dysmenorrhea (24).
Matricaria chamomilla M. chamomoilla is a traditional herbal drug whose extract has anti-inflammatory and antispasmodic effects. It also has a sedative and anti-anxiety effect (25). Many studies have shown the rate of improvement in dysmenorrhea is more for groups using M. chamomoilla than placebo. M. chamomoilla is more effective on relieving dysmenorrhea if it is used before pain begins (26) Three studies examined the effect of M. chamomoilla on primary dysmenorrhea. In the first study, after prescribing M. chamomoilla tea, the rate of anxiety inthe interventiongroup was significantly different from those in the control group after one month (27). In the second study, mefenamic acid was compared with M. chamomoilla in across over treatment which reported that M. chamomoilla was more effective than mefenamic acid in reducing pain (28).
Another study compared the effects of M. chamomoilla with F. vulgare. Consumption of M. chamomoilla and F. vulgare had a significant effect on three symptoms of premenstrual syndrome and dysmenorrhea in which M. chamomoilla was more effective on pelvic and abdominal pain, depression and anger and F. vulgare was more effective on reducing fatigue and lethargy (29).
Valeriana officinalis V. officinalis has been traditionally used as a menstruating and sedative drug since 11 th century (30). Its root and rhizome have valerian essential oil which contains valepotriats. Root of V. officinalis is used as a diuretic, sedative and muscular antispasmodic and valerenic acid of its root has antispasmodic properties (31). Also, the effect of anti-spasmodic valterate, isovalterate on ileum smooth muscle has been confirmed (32). V. officinalis inhibits contractions of cell depolarization well and blocks calcium channels (33).
Two studies have been conducted on V. officinalis, one of which compared the effect of its root with placebo (34) and another compared the effects of V. officinalis with mefenamic acid (35). In the first study, V. officinalis was effective on reducing pain compared to placebo, and in the second study, it had a similar effect to that of mefenamic acid. In one research, systemic symptoms of dysmenorrhea reduced after taking V. officinalis capsules compared to pre-intervention, but the difference was the same as placebo group, except for severity of fainting variable which was significantly different between V. officinalis and placebo groups (32).
In traditional medicine, V. officinalis is known as a menstruating herb, but in a clinical trial, V. officinalis had no effect on duration and severity of bleeding (6).
Cinnamomum zeylanicum C. zeylanicum is from Laurceae family. C. zeylanicum contains mucilage, tannin, a pigment, calcium oxalate, sugar, essential oil and resin. Its physiological effect is attributed to its essential oil and tannin. The main component of cinnamon essential oil is cinnamaldehyde and the essential oil from its bark contains 55 to 57% of cinnamaldehyde and 5 to 18% of eugenol. It has been reported that C. zeylanicum has an antispasmodic effect. Eugenol can also inhibit biosynthesis of prostaglandins and affect inflammation (36).
In a triple-blind study, C. zeylanicum capsule was compared with placebo. In this study, the effect of C. zeylanicum on severity of dysmenorrhea was more than that of placebo. The difference was statistically significant (37).

Stachys lavandulifolia S. lavandulifolia grows in the mountains of Iran and can be abundantly found in Alvand
Mountain. This plant is effective in spasm treatment, is a menstruating agent in women, increasessexuality andcauses abortion and is a pain killer (38).
According to previous studies, S. lavandulifolia can inhibit production of prostaglandins (mediators of pain). S. lavandulifolia extract is also used for stomach pain and painful menstruation (38-40). In a study, 10 g of infusedplant powder was prescribed three times (in Iraniantraditional medicine) and no significant difference was observed in duration of pain and severity of pain before and after using S. lavandulifolia (41).
In another study, S. lavandulifolia affected duration and severity of menstrual pain, but it did not affect systemic symptoms; only reduced diarrhea (42).
Zataria multiflora Z. multiflora is from mint family and its essential oil is thymol and carvacrol. Investigation on ancient physicians' studies has shown that Z. multiflora was used to treat seizures, respiratory diseases, smooth muscular spasm and bloating (43). The most common effect of Z. multiflora is its antispasmodic effect on smooth muscles and its antimicrobial property (44).
Van den Broeke stated that flavonoid of Z. multiflora can inhibit contractions induced by cell depolarization and blocks calcium channel (45).
In a study, the participants were randomly divided to three groups. The first group was treated by placebo, the second by 1% of Z. multiflora essential oil and the third by 2% of Z. multiflora essential oil. The maximum pain reduction was reported in the group with 2% of essential oil (46).
In another study, Z. multiflora leaves had a similar effect to that of mefenamic acid on pain reduction (47).
Mentha piperita M. piperita is used in traditional medicine. The essential oil of this herb is colorless or pale yellow or greenish yellow with odor and pungent taste, obtained from distillation of flowers and fresh twigs.
Experimental studieshave shown that M. piperita oil inhibits contractions induced by cell depolarization and blocks calcium channels and has antispasmodic properties for smooth muscles (48)(49)(50).
In a study, the effect of Supermint ® (mint extract) was compared with that of ibuprofen, both of which reduced pain (51).

Vitex agnus-castus
One of the herbal medicines used for treating menstrual disorders is an herbal drop called Vitagnous ® and a combination which is derived from V. agnus-cactus plants. This plant has a dopaminergic effect. Important combinations of V. agnus-castus, especially its essential oil, affect hypothalamus-pituitary axis and decrease secretion of FSH, release of LH and increase progesterone. Indeed, physiological and pharmacological effects of this drug cause human body to naturally balance hormonal reduction or increase (52) In one study, the effects of Vitagnous ® were compared with those of placebo and it was reported that Vitagnous ® was more effective than placebo in terms of reducing pain intensity (53).
Echinophora platyloba E. platyloba is from Apiaceae family and is one of the endemic plants in Iran. The growth of this plant is mostly distributed in Mediterranean region. Results have shown that the extract of this plant can reduce muscle contraction. Antispasmodic effects of this plant can completely inhibit intestinal irritability (54-55).
Two studies have been conducted in this field, one of which compared the effects of E. platyloba extract with those of placebo (56) and another compared the effects of E. platyloba and fennel on decreasing severity of dysmenorrheal (57). In the first study, E. platyloba extract had a significant difference with placebo in terms of reducing pain intensity, and in the second study, extracts of E. platyloba and F. vulgare could reduce severity of dysmenorrhea during the treatment. The effect of F. vulgare in this case was more than that of E. platyloba.

Achillea willhemsii
A. willhemsii is a plant with anti-prostaglandin effect. It is from Asteraceae (Compositae) family and its anti-inflammatory property of flavonoids in A. willhemsii is due to its inhibitory effect on metabolism of arachidonic acid (58).
In an experimental study, a capsule containing extract of A. willhemsii was prescribed to 70 college students with dysmenorrhea every 6 h. They could reduce the frequency of consumption or dose of drug by 50%, but total daily consumption of capsule should not exceed 4. The results showed that duration of pain in the first three days with treatment reduced significantly compared with the cycles without treatment (59).

Discussion
The aim of this study was to evaluate the efficacy of different herbal remedies on the intensity of primary dysmenorrhea. Most acceptable studies have examined herbal and nutritional treatments. Among them, the number of studies on the use of F. vulgare was more than others. Nineteen trials took 3 to 5 scores of Jadad. In five studies, Jadad score could not be calculated due to the trial type.
In these studies, randomizationmethods, blinding, follow-up, concealment allocation and intention of treatmenthave been used according to Jadad Scale. However, there is not a detailed description of randomization, blinding andfollow-up in most studies. Furthermore, there is the possibility of biased publication because of positive results of all the studies and there is not even one publication with negative results.
Different types of F. vulgare including essence, extract and capsule have been compared with placebo or sedative drugs such as mefenamic acid or other herbs (M. chamomilla and E. platyloba) in order to control pain and in none of these studies, side effects of using the plant have been reported. So, considering numerous studies on F. vulgare, it is suggested as a safe and efficacious plant. It seems that it can be used in the treatment of dysmenorrhea. In a study by Jahromi et al., one patient had increased bleeding (13), but a study by Akhavan et al. showed that F. vulgare did not increase intensity of bleeding and duration of menstruation (60).
piperita and A. willhemsii. Although the results of these studies are positive and these plants are effective on reducing dysmenorrhea, there are not enough studies in this area. Considering their safety, more powerful studies are needed to examine their side effects. It is also suggested to compare different routes of administration for these plants to determine the best route.
Although herbs such as Z. officinale, S. lvandulifolia M. chamomilla and V. officinalis have proved effective, further clinical trials are necessary with the same scale for measuring pain, investigating possible side effects, observing blinding rules and randomization so as to provide a definitive conclusion about their effective use and dose.